Cognitive Decline and Dementia in Patients with Atrial Fibrillation: Update on the CAF and PLUG Dementia Trials

Atrial fibrillation (AF) is the most common sustained arrhythmia, and it is increasing worldwide due to augmented longevity, higher incidences of AF-related risk factors, societal shifts that decrease activity and increase obesity, and broadened use and availability of diagnostic tools.^1,2 Medical therapies to reduce stroke and heart failure, as well as better manage AF-related risk factors, have improved longevity in patients with AF.^{3, 4}

Neurologic disorders, in particular dementia, are also increasing worldwide. In a recent population-based study from Rotterdam, the lifetime risk of dementia, stroke, and Parkinsonism was examined. The lifetime risk for any of these diseases at age 45 was 48.2% in women and 36.2% in men.⁵ There was a higher risk of dementia in women versus men (25.9% vs 13.7%; P<.001), with similar rates of stroke in women and men (19.0% vs 18.9%).⁵

AF is associated with a significant risk for cognitive dysfunction and dementia, both with and without prior clinical stroke (relative risk: 2.43-2.70).^6,7 Although association is likely multifactorial, studies have shown the presence of subclinical cerebral infarcts in many patients with AF.^8-10 Anticoagulation treatment reduces stroke risk in patients with AF, but conveys a persistent risk of macro and micro brain bleeds. As a consequence, cognitive decline, dementia, and stroke may represent a spectrum of brain injuries related to thromboembolism and its treatment in patients with AF.

Stroke risk reduction in most patients with AF is through risk-associated use of anticoagulation. To be effective, anticoagulation must be started early, continued long-term, and effectively used. In a retrospective registry study of patients in Sweden with a hospital diagnosis of AF and no previous diagnosis of dementia, patients on anticoagulant treatment at baseline were associated with having a 38% [HR: 0.62, 95% confidence interval (CI) 0.48–0.81] lower risk of dementia than patients without anticoagulant treatment. The patients most likely to benefit from anticoagulation were those treated within 1 year of AF onset (hazard ratio [HR] = 0.66, or in 1-3 years [HR = 0.80], with little to no benefit for further anticoagulation delays).⁸

In addition to general use, the efficacy of the anticoagulation is also critical to minimize risk of cognitive decline. In a study of 2,605 AF patients managed with warfarin anticoagulation, decreasing categories of time in therapeutic range were associated with increased dementia risk in those with no history of dementia or cognitive decline at anticoagulation start (vs >75%): <25%: HR = 5.34, P<.0001; 26%-50%: HR = 4.10, P<.0001; and 51%-75%: HR = 2.57, P=.001 (Figure 1).⁹

Direct oral anticoagulants (DOACs) have been shown to lower risk of stroke/transient ischemic attack (TIA) in patients with AF. We performed an observational study of 5,254 patients taking a DOAC or warfarin to determine if there was a potential benefit with newer anticoagulants. The composite neurologic endpoint of CVA, TIA, or dementia was 43% more likely in the warfarin group when compared to the DOAC group. Dementia alone was also more common in the warfarin group when compared to DOAC group (0.7% vs 0.3%, P=.03, respectively).¹⁰ In this analysis, dabigatran etexilate was the DOAC with the lowest rates of dementia, despite the longest use in the community (Figure 2).

Dabigatran, which is an oral direct thrombin inhibitor, significantly reduces long-term risk of stroke compared to warfarin.¹¹ Over a median follow-up of 2 years, stroke or systemic embolism was reduced with dabigatran compared to warfarin (1.53% per year [110 mg], 1.1% per year [150 mg] with dabigatran versus 1.69% per year with warfarin). Hemorrhagic stroke was reduced significantly with dabigatran compared to warfarin (HR = 0.26; 95% CI, 0.14-0.49).

The majority of available data regarding the use and efficacy of use of anticoagulation and its associated impact on cognitive function and dementia risk is derived from observational data. As such, the next step in understanding the role of anticoagulation use and risk of cognitive decline is prospective evaluation.

The Cognitive Decline and Dementia in Atrial Fibrillation Patients (CAF) Trial was designed to determine if AF patients randomized to dabigatran will have higher cognition scores studied serially over time and lower rates of dementia compared to dose-adjusted warfarin (INR = 2.0-3.0).¹² AF patients considered for initiation of anticoagulation without a history of moderate-severe cognitive decline or dementia were the target population for the study. In this Vanguard analysis, a study sample size of 120 subjects was targeted to provide a descriptive statistical analysis to determine study feasibility of recruitment, retention, and the likelihood of obtaining the desired outcomes from the prespecified power analysis. The study protocol and workflow are shown in Figure 3.¹²

All study participants have been enrolled and are in different stages of follow-up. The average age of the population is 74 years, and 54% are male. The most common stroke risk factor was hypertension (84%). At the time of enrollment, stroke risk factors were similar between the warfarin versus dabigatran groups. Bleeding risk factors were also similar, with the exception of a trend towards higher prior cancer rates in the warfarin group compared to the dabigatran group (27% vs 12%, P=.06).¹²

We have also recently found that many biomarkers specific to cerebral neurologic injury are elevated in patients with AF. In particular, circulating Tau, stress response marker growth differential factor 15 (GDF15), and astrocyte-specific glial acidic fibrillary protein (GFAP) are elevated. These will be studied prospectively in the CAF trial and their elevation correlated with cognitive scoring.¹³ Multiple other biomarkers of cerebral injury, some of which have been associated with stroke risk, will also be analyzed, including brain natriuretic peptide, troponin T, cystatin C, D-dimer, matrix metalloproteinase (MMP)-9, chemokine ligand 23 (CCL23), endothelial cell adhesion molecule (ESAM), plasma von Willebrand factor, C-reactive protein (CRP), Apolipoprotein E, etc.

The study will include a MRI subset in which patients will undergo brain imaging at enrollment and at 2 years. Specific sequencing will be performed to measure brain volume and to assess for the presence of microbleeds, and clinical or subclinical strokes.

Contemporary treatment to lower stroke risk in patients with AF involves both pharmacologic and nonpharmacologic approaches. Left atrial appendage closure has demonstrated significant benefits in stroke reduction, bleeding risk, and cardiovascular mortality. When the PROTECT AF and PREVAIL trials were combined, 1,114 patients were followed for 4,343 patient-years.¹⁴ Ischemic stroke/systemic embolism rate was higher with left atrial appendage closure compared to routine warfarin therapy, but this difference did not reach statistical significance (HR = 1.71; P=.080). Hemorrhagic stroke was significantly lower in the left atrial appendage closure group (HR = 0.20; P=.002). The composite of stroke, systemic embolism, and cardiovascular death was similar between groups (HR for closure 0.82, P=.27). These absolute event rates compared favorably to the DOAC versus warfarin efficacy trials, and are significantly less than would be expected in the absence of anticoagulation according to the CHADS₂ and CHA₂DS₂-VASc scores of the enrolled cohort.¹⁴

As bleed risk remains pervasive and augments with aging and frailty, even with DOAC treatment, there remains a potential risk of untoward cognitive decline. On the other hand, left atrial appendage closure with long-term platelet therapy has failed to significantly lower embolic stroke risk over extended follow-up and despite improvements in technologies. These risks unique to each therapy approach can significantly impact brain health. For this reason, we initiated the Impact of Percutaneous Left Atrial AppendaGe Closure on the Cognitive Decline and Dementia in Patients with Atrial Fibrillation Trial (PLUG dementia trial) to assess long-term cognition in AF patients that undergo LAA closure with a WATCHMAN device (Boston Scientific). Secondarily, these outcomes will be compared to patients that are treated with standard therapy warfarin or dabigatran as part of the CAF trial. This trial will enroll 60 patients, and to date, has enrolled approximately 20% (Figure 4).

It is our hope that these prospective trials will better inform on the use of different pharmacologic and nonpharmacologic approaches, and provide insight into the long-term impact of a stroke prevention approach on cognitive function, dementia, and in a subset of patients, brain anatomic health and volume. In addition, we hope that these studies will provide insight into the correlation of biomarkers that are specific to cerebral injury, and others associated with systemic vascular disease as well as cognitive dysfunction and dementia. Prospective evaluation of these biomarkers in isolation, combination, or in combination with demographic-based risk factors may provide additional risk stratification in patients with AF and help guide treatment decisions. 

Disclosures: Dr. Bunch has no conflicts of interest to report regarding the content herein. Outside the submitted work, he reports grants from Boehringer Ingelheim, AltaThera, and Boston Scientific.

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